This project will pursue in an outpatient cocaine abuse research clinic two themes of this Medications Development Center. The first theme is that medication development for cocaine may be hampered by viewing cocaine abuse as a unitary syndrome and testing medications on unselected samples. Instead, cocaine abusers may be heterogenous and divisible into subgroups which respond to different treatment approaches. Study I: DESIPRAMINE TREATMENT OF DEPRESSED COCAINE ABUSERS will pursue the hypothesis, derived from promising preliminary data, that desipramine is effective especially in depressed cocaine abusers. Cocaine abusers who meet modified DSM-III-R criteria for depression will enter a 12-week prospective, parallel-groups, randomized, controlled trial of desipramine, followed by a 12-week continuation phase for responders. Depression will be diagnosed with a special version of the Structured Clinical Interview for DSM-III-R, the SCID-SAC, developed for detecting treatable mood disorders in substance abusers. The principal aim will be to determine whether desipramine is effective, compared to placebo, in reducing cocaine use in this select subgroup of depressed cocaine abusers. Other outcome measures will include subjective and physiologic response to cocaine induced cues in the laboratory, cocaine craving, depression, functional impairment, and treatment retention. The second theme is that medication development for cocaine abuse would be aided by improved methods for early Phase II trials in which preliminary indications of efficacy are sought. Simple open label pilot trials have tended to overestimate the promise of new medications. Study II: PRELIMINARY TRIALS OF NOVEL AGENTS FOR COCAINE ABUSE will develop a model for early Phase II testing in which a candidate medication is tested in an integrated program involving both the human laboratory and small scale (N=30) clinical trials. The clinical trials will incorporate placebo control via a multiple-baselines design, and laboratory cue- response as one of the dependent measures. Simultaneously, as part of a currently funded R0-1 (DA06234, Marian Fischman, PI) the same candidate medication will be tested in non-treatment seeking cocaine users in a laboratory cocaine self-administration paradigm, which will also include cue-exposure. A series of novel candidates will be tested, beginning with amoxapine and risperidone, medications which possess combinations of atypical neuroleptic and antidepressant properties. The principal aim will be to integrate data from the laboratory and the clinic to arrive at a preliminary impression of efficacy of the candidate and appropriateness for further Phase II or Phase III trials. Such a model would be useful for testing additional medications as they become available to Medications Development or arise from our work.